Molecular characterization of type I IFN-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance
| Autor: | Bryan C. Fuchs, Jennifer Green, Robin Osterhout, Scott Rp McDonnell, Amy Klova, Jørn S. Jakobsen, Adeela Kamal, Carsten Merkwirth, Reza Beheshti Zavareh |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
IFN resistance Transgene constitutive ISG rAd-IFNα/Syn3 Immune system Interferon medicine Cytotoxic T cell Pharmacology (medical) Cytotoxicity RC254-282 Bladder cancer business.industry Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease IFN biomarker Oncology Molecular Response nadofaragene firadenovec Cancer research type I interferon bladder cancer Molecular Medicine Original Article Signal transduction business medicine.drug |
| Zdroj: | Molecular Therapy Oncolytics Molecular Therapy: Oncolytics, Vol 23, Iss, Pp 547-559 (2021) |
| ISSN: | 2372-7705 |
| DOI: | 10.1016/j.omto.2021.11.006 |
| Popis: | Although anti-tumor activities of type I interferons (IFNs) have been recognized for decades, the molecular mechanisms contributing to clinical response remain poorly understood. The complex functions of these pleiotropic cytokines include stimulation of innate and adaptive immune responses against tumors as well as direct inhibition of tumor cells. In high-grade, Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer, nadofaragene firadenovec, a non-replicating adenovirus administered locally to express the IFNα2b transgene, embodies a novel approach to deploy the therapeutic activity of type I IFNs while minimizing systemic toxicities. Deciphering which functions of type I IFN are required for clinical activity will bolster efforts to maximize the efficacy of nadofaragene firadenovec and other type I IFN-based therapies, and inform strategies to address resistance. As such, we characterized the phenotypic and molecular response of human bladder cancer cell lines to IFNα delivered in multiple contexts, including adenoviral delivery. We found that constitutive activation of the type I IFN signaling pathway is a biomarker for resistance to both transcriptional response and direct cytotoxic effects of IFNα. We present several genes that discriminate between sensitive and resistant tumor cells, suggesting they should be explored for utility as biomarkers in future clinical trials of type I IFN-based anti-tumor therapies. Graphical abstract Jørn Jakobsen and colleagues characterize molecular biomarkers of the anti-tumor effects of IFNα, including a non-replicating adenovirus expressing transgene IFNα2b, on bladder cancer cell lines. Their results will assist design and analysis of future clinical trials to optimize treatment approach to provide maximal benefit to patients with bladder cancer. |
| Databáze: | OpenAIRE |
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